Epidermal growth factor (EGF) is a 53 amino acid cytokine which is proteolytically cleaved from a large integral membrane protein precursor. EGF plays an important role in the growth control of mammalian cells. The amino acid and nucleotide sequences of human EGF (hEGF) are, for example, disclosed in Hollenberg, “Epidermal Growth Factor-Urogastrone, A Polypeptide Acquiring Hormonal States”; eds., Academic Press, Inc., New York (1979), pp. 69-110; or Urdea et al., Proc. Natl. Acad. Sci. USA, 80:7461 (1983). The amino acid sequence of hEGF is also disclosed in U.S. Pat. No. 5,102,789 and copending U.S. patent application Ser. No. 10/820,640 both of which are incorporated herein by reference in their entirety.
Epidermal growth factor receptor (EGFR) is a well known example of receptor tyrosine kinases. Interaction of EGFR with its cognate ligand, EGF, or with structurally related ligands (e.g. tissue growth factor α), leads to dimerization of EGFR and activation of the EGFR kinase domain. This initiates a signaling cascade, leading to cell division. Overexpression of the gene coding for the EGFR has been implicated in a number of cancers including breast, ovarian, and head and neck cancer. Molecules that target EGFR by inhibiting its kinase activity or by interfering with the binding of EGF to EGFR have been shown to inhibit cell proliferation and have been developed as anticancer therapeutics, for example, Iressa® (gefitinib), a tyrosine kinase inhibitor and Erbitux™ (cetuximab), an EGFR-specific monoclonal antibody. Although these therapeutics have been shown to be effective in some cases, there is still a need for novel therapies for EGFR-related cancers.